Nerve gaps/defects are common in various clinical situations, such as trauma and tumor ablation (Millesi H., Surg Clin North Am. 1981; 61:321-340; Millesi H., Scand J Plast Reconstr Surg Suppl. 1982; 19:25-37; Melendez M. et al., Ann Plast Surg. 2001; 46:375-381). Praemer et al. estimated that there are 18 million extremity injuries in the United States each year that result in a substantial number of peripheral nerve injuries (Praemer A. et al., Musculoskeletal conditions in the United States, 1999: 3-162. Park Ridge, Ill. American Academy of Orthopaedic Surgeons). Over the past several decades, considerable research has been performed in an attempt to develop more effective techniques for the management of these injuries.
The current gold standard for nerve repair when a tension-free primary neurorrhaphy is not an option is the interpositional nerve autograft. The advent of nerve grafting in the early 1970s, along with the development of current microsurgical techniques, have greatly improved large nerve gap repair (Millesi H., Orthop Clin North Am. 1970; 2:419-435; Millesi H. et al., J Bone Joint Surg (Am). 1972; 54:727-750; Millesi H. et al., J Bone Joint Surg (Am). 1976; 58:209-218). However, grafting remains a technically demanding procedure associated with long operative times, donor site morbidity, and limited graft availability (Millesi H., Clin Plast Surg. 1984; 11:105-113; Millesi H., Hand Clin. 1986; 2:651-663; Millesi H., Hand Clin. 2000; 16:73-91, viii).
Peripheral nerve recovery following nerve injury and repair are impacted by numerous factors including level of injury, mechanism of disruption, patient age, tension at the repair site, type of repair, and time from injury to repair. Primary neurorrhaphy can be utilized for smaller nerve gaps, usually achieving good results if the anastamosis is performed tension free. Tension at the suture line is detrimental, encouraging connective tissue proliferation and the formation of scar (Dvali L. et al., Clin Plast Surg. 2003; 30:203-221). Sunderland described functional recovery following primary neurorrhaphy of nerve gaps up to 3-5 cm (Sunderland S., Orthop Clin North Am. 1981 April; 12(2):245-266). These repairs were made under slight tension and probably represented the upper limits of nerve gaps that are repairable using this approach. Primary nerve repairs eliminate the disadvantages associated with other techniques, thus, they remain one of the major reconstructive techniques used to manage defects.
For larger nerve defects that cannot be repaired in a tension-free fashion, several methods of interpositional nerve grafting are commonly used. Autogenous nerve grafting is often the first choice. Grafts are usually taken from thin cutaneous sensory nerves. These smaller nerves allow for more consistent revascularization of the graft. However, poor regeneration of motor nerves through sensory nerve grafts has been reported (Nichols C. et al., Exp Neur, 190(2004); 2:347-355).
For these reasons, much research has been focused on the development of effective alternatives to nerve grafting. Lundborg et al. showed increased regeneration rates using autogenous nerve pieces as a conduit filler in a rat model (Nilsson A. et al., Scand J Plast Reconstr Surg Hand Surg. 2005; 39(1):1-6). Trumble et al. successfully used an intact nerve bridge to repair a rat peroneal nerve gap (McCallister et al., J of Reconstr Microsurg. 2005; 3(21):197-206). Autogenous vein has also been studied as a biologic conduit, as has the use of skeletal muscle tissue and tendon as scaffolds (Mersa B. et al., Kulak Burun Bogaz Ihtis Derg. 2004; 13(5-6):103-11; Bertelli J. A. et al., J Peripher Nerv Syst. 2005 December; 10(4):359-68; Brandt J. et al., Scand J Plast Reconstr Surg Hand Surg. 2005; 39(6):321-5; Meek M. F. et al., Tissue Eng. 2004 July-August; 10(7-8):1027-36). Multiple other efforts have been made in biomaterials research and tissue engineering to develop and optimize nerve guidance channels and the scaffolds that fill them (Evans G. R. et al., Anat Rec. 2001; 263:396-404; Dvali L. et al., Clin Plast Surg. 2003; 30:203-221; Meek M. F. et al., J Reconstr Microsurg. 2002; 18:97-109; Schmidt C. E. et al., Annu Rev Biomed Eng. 2003; 5:293-347; Belkas J. S. et al., Neuro Research. 2004; 26:151-160; Bunting S. et al., J Hand Surg (Br). 2005; 30(3):242-247; Katayama U. et al., Biomaterials. 2006; 27(3):505-518).
The potential of nerve conduits to enhance peripheral nerve regeneration while avoiding many of the pitfalls encountered with nerve grafting has stimulated the interest of many researchers. The concept of nerve conduits was first described by Gluck in 1880, who used a glass tube to repair a severed nerve (Gluck T., Arch Klin Chir. 1880; 25:606). Nerve guidance conduits can help prevent the invasion of scar tissue while directing axonal sprouting, and the insertion of an optimized tissue engineering scaffold into the conduit can enhance nerve regeneration (Schmidt C. E. et al., Annu Rev Biomed Eng. 2003; 5:293-347). In the past few decades, multiple biologic and synthetic materials have been used as conduits in an attempt to optimize the microenvironment of the regenerating nerve. The ideal scaffold provides an architecture for regenerative cells, promotes cell attachment, growth and migration, and contributes growth factors to encourage the formation of functional tissue. Acellular scaffolds have become a viable source for tissue engineered conduit matrices. However, these scaffolds, while often containing residual growth factors, have the potential to retard cell infiltration due to their dense architecture.
The need for optimized scaffolds results from the historically poor functional recovery seen with empty nerve conduits used to repair large nerve defects (Belkas J. S. et al., Neurol Res. 2004; 26:151-160; Chen L. E. et al., J Reconstr Microsurg. 1994; 10:137-144; Chiu D. T. et al., Plast Reconstr Surg. 1990; 86:928-934; Chiu D. T., Hand Clin. 1999; 15:667-71, ix; Mosahebi A. et al., Tissu Eng. 2003; 9:209-218). Currently, the use of nerve conduits is limited to smaller diameter nerves with gaps of 3 cm or less (Dvali L. et al., Clin Plast Surg. 2003; 30:203-221). However, when conduits are used in conjunction with an optimized, tissue engineered scaffold nerve regeneration and functional recovery may be enhanced (Schmidt C. E. et al., Annu Rev Biomed Eng. 2003; 5:293-347).
The normal cascade of nerve injury and regeneration has been extensively reviewed (Göran Lundborg. Nerve Injury and Repair, 2nd Edition. Elsevier Inc., Philadelphia, Pa. (2004)). After nerve axotomy, the proximal segment degenerates at least to the nearest node of Ranvier. If a nerve guidance tube is used to repair the newly created gap, the conduit fills with fluid that contains neurotrophic factors and inflammatory cells. Within days, a well organized, longitudinal fibrin matrix forms that contains laminin and fibronectin. This provisional matrix is invaded by macrophages, Schwann cells, fibroblasts, and microvessels from both the proximal and distal nerve stumps. Axons begin to invade this matrix along with additional Schwann cells from the proximal side of the injury and within a few weeks, depending on the size of the gap, reach the distal side of the gap. Extensive remodeling occurs over the course of several months as the regenerating axons reach their targets and become myelinated.
Temporary support of early invading neuronal cells is a classic example of a neuroconductive material and is the mechanism by which most biomaterial fillers act. Neuroconductive biomaterials can support neuronal growth, but do not necessarily enhance cell function, a characteristic reserved for neuroinductive materials. As a consequence, regeneration across large gaps is difficult and highly dependent on the patient-related criteria mentioned earlier. To overcome this, investigators have implemented the use of autologous Schwann cells added to the biomaterial filler (Ansselin A. D. et al., Neuropathol Appl Neurobiol 1997; 23(5):387-98; Rodriguez F. J. et al., Exp Neurol 2000; 161(2):571-84; Strauch B. et al., J Reconstr Microsurg 2001; 17(8):589-95), as well as neurotrophic factors (Lee A. C. et al., Exp Neurol 2003; 184(1):295-303; Walter M. A. et al., Lymphokine Cytokine Res 1993; 12(3):135-41). Isolation of autologous Schwann cells still requires nerve tissue harvested from the patient, and in that sense differs little from autograft. Stem cells have been viewed as a solution to this dilemma and have been used in both differentiated and undifferentiated states (Tohill M. et al., Biotechnol Appl Biochem 2004; 40(1):17-24). While this approach has garnered much attention, particularly for application to the central nervous system, neuronal phenotypes are among the most difficulty to reliably differentiate in high yields from adult stem cells, the most likely source for near-term clinical application to peripheral nerve repair (Kokai L. E. et al., Plast Reconstr Surg 2005; 116(5):1453-60; Chen Y. et al., Cell Mol Life Sci 2006; 63(14):1649-57).
Therefore, there remains a need for optimal biomaterial fillers that promote both the regrowth and functional recovery of injured nerves.